1. Field of the Invention
This invention relates to vesamicol derivatives that have anticholinergic properties.
2. Description of the Related Art
Cholinergic neurotransmission is comprised of several functional units. These include: 1) sequestration, by presynaptic cholinergic terminals, of choline, the precursor for the synthesis of acetylcholine (ACh); 2) the synthesis of ACh catalyzed by choline acetyltransferase (ChAT); 3) the storage of ACh in synaptic vesicles; 4) release of neurotransmitter into the synapse in response to a stimulus; and 5) degradation of ACh within the synaptic cleft, mediated by acetylcholinesterase (AChE), to regenerate choline. The latter is subsequently recycled. Given the multivariate nature of this system, regulation of cholinergic function may be accomplished in multiple ways. The synthesis of ACh takes place in the cytoplasm. However, ACh is subsequently stored in special organelles called synaptic vesicles. In response to a stimulus, these vesicles fuse with the presynaptic membrane and release their contents into the synapse. Neurotransmitter is characteristically released in discrete amounts or quanta. Therefore, the synaptic vesicle largely defines the unit of ACh release. The release of neurotransmitter is in turn inextricably linked to its storage. Consequently, interference with storage mechanisms provides a means of modulating the release of acetylcholine and thereby modulating cholinergic function.
The lipophilic amino alcohol 2-(4-phenylpiperidino)cyclohexanol (1, vesamicol, AH 5183) induces respiratory paralysis, spasms and death in laboratory animals (Brittain et al, 1969). The pharmacological activity of vesamicol is attributed to its ability to block cholinergic neurotransmission. The latter process is accomplished by the binding of vesamicol to a unique site, the vesamicol receptor, on the cholinergic synaptic vesicle. The vesamicol receptor is functionally linked to the vesicular ACh transporter (Marien et al., 1991), a protein complex which transports ACh from the cytoplasm into the vesicle. Occupancy of the vesamicol receptor by vesamicol or its analogs blocks the storage and subsequent release of ACh, thereby effectively shutting down cholinergic neurotransmission (for review, see Marshall & Parsons, 1987; Parsons et al., 1993). Vesamicol selectively inhibits the storage and release of neurotransmitter without directly affecting the synthesis of this neurotransmitter. The foregoing observations suggest that selective blockade of the vesamicol receptor may provide a means of modulating cholinergic function in animals.
In spite of its potency as an anticholinergic, vesamicol exhibits .alpha.-adrenoceptor activity at higher doses. The poor selectivity of this compound limits its use as a selective anticholinergic. Although Rogers et al. (1989) expressed a need for more potent and selective analogs, they failed to suggest methods for increasing potency. Previous studies by Rogers et al. (1989) have shown that 2-aminoethanol fragment of vesamicol is essential for molecular recognition at the vesamicol receptor. In addition, these authors showed that potent VR ligands could be obtained by substitution at the C4-carbon of vesamicol and by ring fusion on the cyclohexyl fragment of vesamicol. In a subsequent study, Efange et al. (1991) reported the synthesis of acyclic vesamicol analogs represented by HBrPP (2a)(FIG. 1). Although 2a lacks the cyclohexyl moiety found in vesamicol, the former was nevertheless found to be equipotent with vesamicol. The latter observation was attributed to the ability of this acyclic analog to adopt a conformation similar to that found in the fused analog ABV (2b), a potent VR ligand. Further exploration of the structure-activity relationships of vesamicol receptor ligands has yielded trozamicol, 3, (Efange et al., 1993), the parent structure for a new class of vesamicol receptor ligands. Although trozamicol is a poor ligand for vesamicol receptor, N-benzylation of trozamicol yields potent ligands such as MIBT ,4, (Efange et al., 1993). In the present study we disclose a new approach to the development of potent vesamicol receptor ligands for modulating presynaptic cholinergic function.
The vesamicol structure may be divided into three major fragments: the cyclohexyl (fragment A), piperidyl (fragment B), and phenyl (fragment C) moieties. In their original investigation, Rogers et al. (1989) carried out extensive modification of all three fragments with varying results. In general, single-point modifications in fragment B or C were found to yield analogs of slightly lower or comparable potency relative to vesamicol. On the other hand, those analogs which represented drastic structural alterations of the piperidyl and phenyl moieties (fragments B and C) were found to be inactive. For example, chlorovesamicol (1b) and nitrovesamicol (1c) and the piperazine-containing analogs 5a-c were between two and eight times less potent than vesamicol. However, the tetrahydroisoquinoline analog 6a was found to be 125 times less active than vesamicol. In addition, the spirofused compound 6b and other analogs (e.g., 7a and 7b) which incorporate fragments B and C in a complex molecule were also found to be inactive. These results clearly suggested that drastic structural modification of fragments B and C would not be fruitful.
The art described in this section is not intended to constitute an admission that any patent, publication or other information referred to herein is "prior art" with respect to this invention, unless specifically designated as such. In addition, this section should not be construed to mean that a search has been made or that no other pertinent information as defined in 37 C.F.R. .sctn. 1.56(a) exists.